ES2698396T3 - Methods to treat gout outbreaks - Google Patents

Abstract

A compound that is (-)-halofenate, or (-)-halofenic acid or a pharmaceutically acceptable salt thereof, substantially free of its (+)-enantiomer, for use in treating a flare of gout or for reducing the number , the frequency, duration, or intensity, of gout flares experienced by a subject during initiation or maintenance of uric acid-lowering therapy.

Description

DESCRIPTION

Methods to treat gout outbreaks

Background

This request refers to the treatment, including prevention, of gout outbreaks.

Schlesinger N. (Drugs, 2004, 64 (21): 2399-416) discloses three separate stages in the management of gout. This publication emphasizes the distinction between therapy to reduce acute inflammation in acute gout and therapy to control hyperuricemia in patients with chronic gouty arthritis. It is said that NSAIDs are the preferred treatment in attacks of acute gout, and it is said that non-pharmacological treatments are useful. Various drugs are proposed for a prolonged reduction of uric acid in serum to control chronic gout.

Summary

This application describes methods for treating a gout outbreak experienced by a subject comprising administering to the subject a compound of Formula (I)

wherein R is selected from the group consisting of a hydroxy, lower aralkoxy, lower alkylamino-lower alkoxy, lower alkanoid-lower alkoxy, benzamido-lower alkoxy, ureido-lower alkoxy, N'-lower alkyl-ureidoalkoxy lower, carbamoyl-lower alkoxy, lower alkoxy substituted with halofenoxy, phenoxy substituted with carbamoyl, carbonyl-lower alkylamino, N, N-di-lower alkylamino-lower alkylamino, lower alkylamino substituted with halo, lower alkylamino substituted with hydroxy, substituted lower alkylamino with lower alkanoyloxy, ureido and lower alkoxycarbonylamino; and each X is independently a halogen, or a pharmaceutically acceptable salt thereof.

Also disclosed are methods for reducing the number, duration, frequency or intensity of the gout shoots experienced by a subject comprising administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject. Also disclosed is the treatment of hyperuricemia in a subject with droplet comprising administering to a subject in need thereof a compound of Formula (I), wherein the dose, frequency and duration of administration are effective in reducing the number , duration, frequency or intensity of gout outbreaks experienced by the subject during the duration. Also disclosed are methods for providing a (-) - halofenic acid subject with an intraday maximum to trough ratio of about 2.0 or less. Other aspects are provided below. The invention is defined in claim 1. Preferred features are defined in the dependent claims.

Uric acid reducing agents, such as allopurinol and febuxostat, generally increase the number, duration, frequency or intensity of gout flares at the start of treatment, and this exacerbation may last several weeks to months after the start of treatment. said therapy. The uric acid reducing agents often require a dose adjustment strategy in which the dose is progressively increased to the therapeutic dose in order to minimize the number, duration, frequency or intensity of the outbreaks. During this period, treatment of the outbreak or prophylaxis with an additional therapeutic agent, such as a non-steroidal anti-inflammatory agent (NSAID) or colchicine, is often recommended. During prolonged maintenance use of urate reduction therapy, outbreaks may also be precipitated by fluctuations in uric acid levels caused by noncompliance with prescription instructions. The advantages of current methods include decreasing the number, duration, frequency or intensity of outbreaks experienced by the patient (eg, during the initiation or maintenance of therapy for the reduction of uric acid), decreased the need for dose adjustment and reduction of the quantity or duration of additional antibrote drugs.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing average values of trough plasma concentration of (-) - halofenic acid during and after a 30-day oral dosing schedule of 400 mg of arhalofenate.

Fig. 2 is a graph showing the mean and standard deviation (SD) of plasma concentrations of (-) - halofenic acid on days 15 and 30 after daily oral administration of 400 mg of arhalophenate in 20 human subjects .

Fig. 3 is a graph showing the reduction of serum uric acid in subjects over time after a daily dose with arhalophenate.

Fig. 4 is a graph showing the effect of (-) halofenic acid on the reduction of messenger RNA encoding the proinflammatory cytokine IL-1 p in primary mouse macrophages stimulated with lipopolysaccharide (LPS).

Fig. 5 is a graph showing the effect of (-) - halofenic acid in reducing the secretion of the proinflammatory cytokine IL-1 p from primary mouse macrophages stimulated with lipopolysaccharides.

Fig. 6 is a graph showing the average reduction of high sensitivity C-reactive protein (hs-CRP) levels in human subjects after treatment with (-) - halofenate 600 mg.

FIG. 7 is a graph showing the average percent reduction of high sensitivity C-reactive protein (hs-CRP) levels in human subjects after treatment with (-) - halofenate 600 mg.

Detailed description

As used in accordance with the present disclosure, it will be understood that the following terms, unless otherwise indicated, have the following meanings:

"Approximately" when rating a number, refers to an interval of plus or minus ten percent of that value or number, unless otherwise indicated. Without limiting the application of the doctrine of equivalents as to the scope of the claims, each number must be interpreted in light of factors such as the number of significant digits indicated and the form or method (eg, instrumentation, sample preparation). , etc.) used to obtain that number.

"Administer" or "administration" refers to the act of administering a drug, prodrug or therapeutic agent to a subject. Exemplary administration routes are discussed below.

"Acute drop" refers to the drop present in a subject with at least one symptom of gout (eg, podagra or other gouty arthritis, gout flare, gout attack).

"Chronic gout" refers to gout present in a subject who has recurrent or prolonged gout flares, tophi formation, chronic inflammatory arthritis or joint deterioration associated with gout, and includes periods after acute gout recovery and between attacks of acute gout (ie, intercritical gout).

"Composition" or, indistinctly, "formulation" refers to a preparation containing a mixture of various excipients and key ingredients that provide a relatively stable, desirable and useful form of a compound or drug.

The prefixes "d" and "l" or (+) and (-) are used to designate the sign of rotation of plane polarized light by the compound, meaning (+) od that the compound is "dextrorotatory" and meaning (- ) or 1 that the compound is "levorotatory". For a given chemical structure, these isomers or "optical isomers" are identical, except that they are mirror images of each other. In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule on its chiral center (s). There is no correlation between the nomenclature for absolute stereochemistry and for the rotation of one enantiomer (ie, the R isomer can also be isomer 1). A specific optical isomer may also be referred to as an "enantiomer", and a mixture of such isomers is often called an "enantiomeric" or "racemic" mixture. See, p. eg, A. Streitwiesser & CH Heathcock, INTRODUCTION TO ORGANIC CHEMISTRY, 2nd edition, chapter 7 (MacMillan Publishing Co., USA).

1981). Optical rotation [a] D of (-) - halofenate was measured in methyl alcohol.

"Elevated serum uric acid level" means a level of serum uric acid greater than normal and, in patients with gout, generally refers to a level of serum uric acid greater than or equal to approximately 6 mg / dl . In some cases, elevated serum uric acid levels are above the average level in a given population, such as those of a particular gender or age.

"Effective amount" refers to an amount required (i) at least in part to achieve the desired response in a subject; (ii) delay or prevent the onset of a particular condition that is treated in a subject; or (iii) or to inhibit or prevent the progression of a particular condition that is treated in a subject. The effective amount for a particular subject varies according to the health and physical condition of the subject to be treated, the taxonomic group of the individual to be treated, the degree of protection desired, the formulation of the composition, the evaluation of the medical situation, and other relevant factors. It is expected that the quantity will be included in a relatively broad range that can be determined through routine tests.

"First urate reducing agent" refers to a compound of any of Formulas (I), (II), (III), or (IV) or a therapeutically acceptable salt or prodrug thereof. For clarity, this term does not imply any aspect or temporal relationship, p. eg, with a second urate reducing agent.

"Bud" or "gout outbreak" refers to a symptom of gout associated with a sudden onset of pain and inflammation, especially in peripheral joints, such as the toes or fingers.

"Gout" refers to a group of disorders or symptoms that are most commonly associated with the accumulation of uric acid due to excessive production of uric acid or a reduced ability of the kidney to excrete uric acid. Gout is often characterized by the deposition of urate crystals (uric acid or salts thereof, eg, monosodium urate) in the joints (gouty arthropathy) or soft tissue (tophi). "Gout" as used herein includes acute gout, chronic gout, moderate gout, refractory gout, and severe gout.

"Inflammation associated with gout" refers to local or systemic inflammation due to immune responses to the deposition of urate crystals.

"Halofenate" refers to the compounds of Formula (III) below, ie 2-acetylaminoethyl ester of (4-chlorophenyl) - (3-trifluoromethylphenoxy) -acetic acid (also referred to as 2-acetamidoethyl ester of 4-chlorophenyl- (3-trifluoromethylphenoxy) -acetic acid The term halofenate and the corresponding chemical names include both the (+) enantiomer and (-) enantiomer of the compounds of Formula (III), as well as mixtures thereof, unless otherwise specified another thing.

"Halofenic acid" and "CPTA" refer to compounds of Formula (IV), ie 4-chlorophenyl- (3-trifluoromethylphenoxy) -acetic acid [also called 2- (4-chlorophenyl) -2- (3- (trifluoromethyl) phenoxy) acetic], as well as their pharmaceutically acceptable salts. The term "halofenic acid" and the corresponding chemical names include both the (+) enantiomer and (-) of the compounds of Formula (IV), as well as mixtures thereof, unless otherwise specified.

"Hyperuricemia" refers to an elevated level of serum uric acid (see above).

"Impaired renal function" refers to a medical condition in which the kidneys do not properly filter toxins and waste products from the blood. Impaired renal function can take the form of acute kidney injury or chronic kidney disease (ie, CKD1-5).

"Moderate droplet" refers to the drop present in a subject who has at least two outbreaks of gout in the last 12 months.

"Pharmaceutically acceptable" refers to what is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and is not desirable neither biological nor otherwise, and includes that which is acceptable for veterinary or human pharmaceutical use .

"Pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts and includes solvated and unsolvated forms. Representative non-limiting lists of pharmaceutically acceptable salts can be found in SM Berge et al., J. Pharma Sci., 66 (1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), p. 732, Table 38-5.

"Pharmaceutically acceptable acid addition salt" refers to salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid , glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid , and similar.

"Pharmaceutically acceptable base addition salt" refers to salts prepared from the addition of an inorganic base or an organic base to the free acid. Salts obtained from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like salts. Salts obtained from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines, including substituted amines of natural origin, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.

"Refractory droplet" refers to gout in patients who do not respond or respond poorly to one or more second urate reducing agents, or who have experienced or have a higher risk of experiencing an adverse event thereof. The terms "does not respond" and "responds poorly" in this context include (1) no reduction or nonsignificant reduction of uric acid in serum, (2) the inability to reach a level of uric acid in target serum (e.g. , as determined by a physician or other medical practitioner) and (3) the persistence of one or more gouty conditions or symptoms, such as gout flares, gouty tophi, gouty arthritis, or other associated conditions, regardless of any decrease in serum levels of uric acid.

"Second urate reducing agent" refers to a therapeutic agent that reduces serum levels of uric acid that is not a first urate reducing agent. The second urate-reducing agents include the currently available agents (ie, an agent approved by the FDA or other appropriate regulatory authority at the time of filing this application) that reduce serum uric acid, as well as compounds currently in development or under regulatory review. Below are examples of second urate reducing agents. For clarity, this term does not imply any aspect or temporal relationship, p. eg, with a first urate reducing agent.

"Subject" and "patient" refer to animals such as mammals, including humans, other primates, domesticated animals (eg, dogs, cats), farm animals (eg, horses, cattle, goats) , sheep, pigs), rats and mice.

"Severe droplet" refers to the gout present in a subject that has tophaceous deposits on the joints, skin or kidneys that result in chronic arthritis, joint destruction, subcutaneous tophi or renal dysfunction and, in some cases, deformity and / or disability later.

"Substantially free of" when used in reference to (-) - halofenate or (-) - halofenic acid (or a salt thereof) that is substantially free of the corresponding (+) enantiomer (i.e., (+) - halofenate, (+) - halofenic acid, or a salt thereof), refers to a composition containing a high proportion of an (-) enantiomer of a compound in relation to the (+) enantiomer. In one embodiment, the expression means that, by weight, the compound included in the composition is at least 85% (-) enantiomer and at most 15% (+) enantiomer. In one embodiment, the expression means that, by weight, the compound included in the composition is at least 90% (-) enantiomer and at most 10% (+) enantiomer. In other embodiments, the term means that, by weight, the compound included in the composition is at least 91% enantiomer (-) and at most 9% enantiomer (+), at least 92% enantiomer (-) and as maximum 8% enantiomer (+), at least 93% enantiomer (-) and maximum 7% enantiomer (+), at least 94% enantiomer (-) and maximum 6% enantiomer (+), less 95% enantiomer (-) and at most 5% enantiomer (+), at least 96% enantiomer (-) and at most 4% enantiomer (+), at least 97% enantiomer (-) and as maximum 3% enantiomer (+), at least 98% enantiomer (-) and at most 2% enantiomer (+), or at least 99% enantiomer (-) or greater than 99% enantiomer (-). Other percentages of the (-) and (+) enantiomers can also be provided. These percentages are based on the amount of the enantiomer with respect to the total amount of both enantiomers of the compound in the composition.

"Therapeutically effective dose", "therapeutically effective amount" or, indistinctly, "pharmacologically acceptable dose" and "pharmacologically acceptable amount" mean that a sufficient amount of a therapeutic agent, therapeutic agents or metabolites thereof will be present in order to achieve a desired result, p. For example, reduce uric acid levels to a target or treat gout in its various forms or treat conditions associated with hyperuricemia.

"Treatment" and "treating" a disease, disorder, condition or symptom refers to (1) preventing or reducing the risk of developing the disease, disorder or condition, i.e., causing the clinical symptoms of the disease, disorder or The condition does not develop in a subject who may be exposed or predisposed to the disease, disorder or condition, but who does not yet experience or show symptoms of the disease, disorder or condition (ie, prophylaxis); (2) inhibit the disease, disorder or condition, i.e., stopping or reducing the development of the disease, disorder or condition or its clinical symptoms; and (3) alleviating the disease, disorder or condition, i.e., causing regression, reversion or improvement of the disease, disorder or condition or reducing the number, duration, frequency or intensity of one or more of its clinical symptoms ( eg, a drop outbreak). The term "treatment" can be used as a synonym.

"Urate" refers to uric acid (7,9-dihydro-1H-purine-2,6,8 (3H) -trione) and ions and salts thereof.

This application describes methods for treating a gout outbreak comprising administering to the subject a compound of Formula (I)

wherein R is selected from the group consisting of a hydroxy, lower aralkoxy, lower alkylamino-lower alkoxy, lower alkanoid-lower alkoxy, benzamido-lower alkoxy, ureido-lower alkoxy, N'-lower alkyl-ureidoalkoxy lower, carbamoyl-lower alkoxy, lower alkoxy substituted with halofenoxy, phenoxy substituted with carbamoyl, carbonyl-lower alkylamino, N, N-di-lower alkylamino-lower alkylamino, lower alkylamino substituted with halo, lower alkylamino substituted with hydroxy, lower alkylamino substituted with lower alkanoyloxy, ureido and lower alkoxycarbonylamino; and each X is independently a halogen, or a pharmaceutically acceptable salt thereof.

The compound can be a compound of Formula (II)

wherein R2 is selected from the group consisting of phenyl-lower alkyl, lower alkanamido-lower alkyl and benzamido-lower alkyl; and each X is independently a halogen, or a pharmaceutically acceptable salt thereof.

In some aspects, the compound is a compound of Formula (III), also called halofenate

or a pharmaceutically acceptable salt thereof.

In other aspects, the compound is a compound of Formula (IV), also called halofenic acid

or a pharmaceutically acceptable salt thereof.

It should be borne in mind that any carbon atom with unsatisfied valences in the formulas and examples herein is assumed to have the hydrogen atom to satisfy the valences.

In certain embodiments, the compound is a compound that generates the compound of Formula (IV) or a pharmaceutically acceptable salt thereof through a chemical reaction after being administered, as discussed in greater detail below.

The compound can be the (-) enantiomer of a compound of Formulas (I), (II), (III), or (IV). In certain embodiments, the compound is (-) - halofenate (i.e., (-) - (R) - (4-chloro-phenyl) - (3-trifluoromethyl-phenoxy) -acetic acid 2-acetylaminoethyl ester, also called arhalophenate). In other embodiments, the compound is (-) - halofenic acid (ie, (-) - 4-chlorophenyl- (3-trifluoromethylphenoxy) acetic acid) or a pharmaceutically acceptable salt thereof. The (-) - halofenate, (-) - halofenic acid, or pharmaceutically acceptable salt thereof is substantially free of the corresponding (+) enantiomer.

The enantiomers (stereoisomers) of the compounds of Formulas (I), (II), (III) or (IV) and their pharmaceutically acceptable salts can be prepared using reactants or reagents or catalysts in their only enantiomeric form in the process whenever possible. or resolving the mixture of stereoisomers by conventional methods including the use of microbial resolution, resolving the diastereomeric salts formed with chiral acids or chiral bases and chromatography using chiral supports. See also U.S. Patent No. 7,199,259 (Daugs), U.S. Pat. No. 6,646,004; 6,624,194; 6,613,802; and 6,262,118 (each by Luskey et al.), U.S. Pat. No. 7,714,131 (Zhu et al.), U.S. Pat. No. 7,432,394 (Cheng et al.) and the US publication. No. 2010/0093854 (Broggini et al.)

The chemical synthesis of racemic mixtures of (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives can also be carried out by the methods described in U.S. Pat. No. 3,517,050. Individual enantiomers can be obtained by resolution of the racemic mixture of enantiomers using conventional means known and used by those skilled in the art. See, p. eg, J. Jaques et al., in ENANTIOMERS, RACEMATES, AND RESOLUTIONS, John Wiley and Sons, New York (1981). Other conventional resolution methods known to those skilled in the art can also be used, including but not limited to, simple crystallization and chromatographic resolution, (see, eg, STEREOCHEMISTRY OF CARBON COMPOUNDS (1962) Eliel, McGraw Hill; Lochmuller, Chromatography 113, 283-302 (1975)). In addition, halofenate, halofenic acid or a pharmaceutically acceptable salt thereof, that is, the optically pure isomers, can be prepared from the racemic mixture by enzymatic biocatalytic resolution. Enzymatic biocatalytic resolution has been generally described above (see, e.g., U.S. Patent Nos. 5,057,427 and 5,077,217). Other generic methods for obtaining enantiomers include stereospecific synthesis (see, e. G., Li AJ et al., Pharm. Sci. 86, 1073-1077 (1997)).

Although not wishing to be bound by any particular theory, it is thought that several properties of the compounds described herein explain their successful use in the treatment (including reduction of number, duration, frequency or intensity) of the outbreaks. of gout, for example during the initiation and maintenance of the use of these compounds to reduce uric acid: (1) its pharmacokinetic profile and (2) its anti-inflammatory properties, including the inhibitory effect on interleukin-lbeta (IL-1 b). ) and the reduction of high sensitivity C-reactive protein, and (3) its ability to block the entry of uric acid into a cell.

Figures 1-2 show the pharmacokinetic profile of (-) - halofenic acid. Fig. 1 shows the minimum mean plasma concentration values of (-) - halofenic acid during and after a 30-day oral dosing schedule of 400 mg of arhalofenate. Fig. 2 shows the values of the mean plasma concentration and standard deviation (SD) of (-) - halofenic acid on days 15 and 30 after the daily oral administration of 400 mg of arhalofenate. These figures demonstrate a long half-life with sustained drug levels present for several days after the final dose and a relatively constant intra-day plasma concentration. It is expected that the plasma concentration of (-) - halofenic acid correlates with the plasma concentration of uric acid. Consequently, it is expected that the long half-life and the low ratio between the intraday peak and valley result in progressively corresponding changes in serum uric acid during the initiation and maintenance of the use of therapy. Fig. 3 demonstrates the reduction of serum uric acid over time with various doses of arhalophenate, and supports this theory. It is believed that large or rapid changes in serum uric acid (as a result of, for example, certain second urate reducing agents, eg, allopurinol, febuxostat and others) can trigger outbreaks of gout or result in longer outbreaks. , more frequent or more intense, for example, during and for several weeks and months after the start of said agents, or with the non-compliance to the daily use of said agents. Therefore, the pharmacokinetic profile of (-) - halofenic acid should contribute to the successful use of the compounds of Formulas (I), (II), (II), (III) and (IV) and pharmaceutically acceptable salts thereof in the prevention of gout outbreaks (for example, during certain periods such as the first weeks to months after the start of administration), in comparison with other urate-reducing treatments.

The compounds of Formulas (I), (II), (III) and (IV) and pharmaceutically acceptable salts thereof also have an inhibitory effect and block the key pathways of inflammation. Inflammasomes are activated molecular platforms after cell infection or stress that trigger the maturation of proinflammatory cytokines such as interleukin-lbeta (IL-1 p) to activate innate immune defenses. Therefore, inhibitors of IL-1 p may have a role in the therapy of gout. See, p. eg, A. So. and N. Busso, Ann. Rheum. Dis., 68 (10) (2009) and references cited therein. Fig. 4 shows the effect of (-) - halofenic acid to decrease the messenger RNA encoding the proinflammatory cytokine IL-1 p in primary mouse macrophages stimulated with lipopolysaccharides (LPS). We hypothesize that (-) - halofenic acid exerts its anti-inflammatory effects by binding to the transcription factor PPAR- ^y and in this bound form interacts directly with and stabilizes the transcriptional machinery located in the promoter for IL-1 p. In this way, activation of the Il-1p promoter in response to treatment with LPS is prevented by (-) - halofenic acid. Fig. 5 shows the effect of (-) - halofenic acid in reducing the secretion of the proinflammatory cytokine IL-1 p from primary mouse macrophages stimulated with lipopolysaccharides.

High sensitivity C-reactive protein (hs-CRP) is another marker of inflammation. Fig. 6-7 show that the administration of (-) - halofenate in human subjects reduced hs-CRP, which supports the effectiveness of the compounds of Formulas (I), (II), (III) or (IV) or pharmaceutically acceptable salts or prodrugs thereof to treat bead sprouts.

An additional mechanism that contributes to the successful treatment of gout flares is blocking the entry of uric acid into a cell. The transport of uric acid to the cells is mediated by a series of uric acid transporters that include URAT1, GLUT9 (SLC2A9), OAT4 and OAT10. For example, in adipocytes, uric acid increases the expression of proinflammatory cytokines such as MCP-1 (Baldwin et al., Diabetes 60 1258-1269 (2011)). It is hypothesized that (-) - halofenic acid is an inhibitor of URAT1 and, as such, the administration of compounds of Formulas (I), (II), (III) and (IV) and pharmaceutically acceptable salts thereof are expected to decrease inflammatory responses induced by uric acid in cells, including, for example, adipocytes, macrophages and endothelial cells.

The methods described herein include reducing the number, duration, frequency or intensity of one or more bead outbreaks, the methods comprising administering to a subject in need thereof a compound of any of Formulas (I), ( II), (III) or (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (-) - halofenate, (-) - halofenic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the number, duration, frequency or intensity of the gout shoots experienced by the subject are reduced in relation to that experienced by the subject before said administration is initiated. In other embodiments, the number, duration, frequency or intensity of the gout shoots experienced by the subject are reduced in relation to the number, duration, frequency or intensity of the gout shoots experienced by the subject when the subject has previously been subjected to a urate reduction therapy with a second urate reducing agent. In certain methods for reducing the number, duration, frequency or intensity of the gout flares experienced by the subject, the amount or duration of the administration of any additional therapeutic agent (e.g., a prophylaxis agent of the outbreak as a non-steroidal anti-inflammatory drug (NSAID) or colchicine) is reduced, and in such other methods such an additional therapeutic agent (eg, NSAID or colchicine) is not administered.

The second urate reducing agent can be any agent that reduces serum levels of uric acid other than a first urate reducing agent (ie, it is not a compound of any of Formulas (I), (II), (III) ) or (IV) or a pharmaceutically acceptable salt thereof). These second urate reducing agents include inhibitors of uric acid production (eg, xanthine oxidase inhibitors and purine nucleoside phosphorylase inhibitors), uricosuric and uric acid agents. Inhibitors of xanthine oxidase include, but are not limited to: allopurinol, febuxostat, oxipurinol, tisopurine, an inositol and propolis. In some embodiments, the xanthine oxidase inhibitor is allopurinol, febuxostat, oxipurinol, tisopurine, inositol, phytic acid, myoinositol, kaempferol, myricetin, and quercetin. Allopurinol (1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one), an inhibitor of xanthine oxidase, is the current first-line care pattern for reducing urate levels. Another inhibitor of xanthine oxidase, febuxostat (2- (3-cyano-4-isobutoxyphenyl) -4-methyl-1,3-thiazole-5-carboxylic acid), was approved for the treatment of gout in February 2009. Purine nucleoside phosphorylase (PNP) inhibitors represent a relatively new approach to reducing serum levels of uric acid in patients with hyperuricaemia, gout, and related conditions. In some embodiments, the PNP inhibitor is forodesin (BCX-1777) (BioCryst Pharmaceuticals, Inc.). In other embodiments, the PNP inhibitor is BCX-4208 (7 - (((3R, 4R) -3-hydroxy-4- (hydroxymethyl) pyrrolidin-1-yl) methyl) -3H-pyrrolo [3,2- d] pyrimidin-4 (5H) -one) (BioCryst Pharmaceuticals, Inc.). Monotherapy with BCX4208 administered at 40, 80, 120, 160 and 240 mg / day has been shown to rapidly and significantly reduce serum uric acid in patients with gout. The uricosuric agents improve the renal excretion of uric acid and generally act by reducing the absorption of uric acid from the proximal tubule of the kidney to the blood, p. eg, inhibiting urate transporters, p. eg, SLC22A12. Uricosuric agents include, but are not limited to, probenecid, 2 - ((5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-yl) thio) acetic acid ( RDEA594, lesinurad), 4- (2 - ((5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-yl) thio) acetamido) -3-chlorobenzoate of potassium (RDEA806), RDEA684, benzbromarone, sulfinpyrazone, amlodipine, atorvastatin, fenofibrate, guaifenesin, losartan, adrenocorticotropic hormone and cortisone. Probenecid is the most commonly used uricosuric agent in the United States. and it can be administered in combination with allopurinol to some gout patients. Benzbromarone and sulfinpyrazone are also used as first-line uricosuric agents. Guaifenesin, losartan, atorvastatin, amlodipine, adrenocorticotropic hormone (ACTH or corticotropin), fenofibrate and cortisone also have uricosuric effects. The enzymes uricase or urate oxidase are found in many mammals but not in humans. They can reduce uric acid levels by converting uric acid to allantoin, a benign metabolite that is easily excreted in the urine. Uricase enzymes include, but are not limited to, rasburicase or a pegylated uricase enzyme (PEG-uricase). In some embodiments, the pegylated uricase enzyme is Krystexxa® (PURICASE®, pegloticase) (Savient Pharmaceuticals, Inc.) which is approved in the USA for the treatment of chronic gout in refractory to conventional therapy of adult patients.

In some embodiments, the number of gout shoots experienced by the subject is reduced in relation to the number, duration, frequency or intensity of gout shoots experienced by the subject when the subject has been previously subjected to a therapy of gout. reduction of urate with a second urate reducing agent, in which the second urate reducing agent is allopurinol, febuxostat, lesinurad or BCX4208.

Certain methods provide for the treatment or management of hyperuricemia in a subject with gout and reduce the number, duration, frequency or intensity of gout flares experienced by the subject. These methods comprise administering to a subject in need thereof a compound of any of Formulas (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (-) - halofenate, (-) - halofenic acid or a pharmaceutically acceptable salt thereof.

In various embodiments, the methods described herein reduce serum uric acid levels in a subject by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, Approximately 40% about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% or higher, compared to the serum levels of Uric acid in the subject prior to administration of the methods described herein. In various embodiments, serum uric acid levels decrease from about 5% to about 50%, decrease from about 25% to about 75%, or decrease from about 50% to about 99%. Methods for determining uric acid levels in serum are well known in the art and are often measured as part of a conventional chemistry panel study of blood serum samples.

In some embodiments, the methods of the present disclosure reduce the levels of serum uric acid in a subject to about 7 mg / dL or less, to about 6.5 mg / dL or less, to about 6 mg / dL or less, at about 5 mg / dL or less, at about 4 mg / dL or less, or at about 3 mg / dL or less compared to serum levels of uric acid in the subject prior to administration of the methods or compositions described in present document. In some embodiments, the methods of the present disclosure reduce serum levels of uric acid in a subject by 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 1.5, 2 , 0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0 , 8.5, 9.0, 9.5 or 10.0 mg / dL, or more, compared to the serum levels of uric acid in the subject prior to administration of the methods or compositions described herein. In other embodiments, the methods described herein reduce serum uric acid levels between 0.1 and 10.0 mg / dL, between 0.5 and 6.0 mg / dL, between 1.0 and 4, 0 mg / dl or between 1.5 and 2.5 mg / dl. The appropriate level of serum uric acid may vary depending on the subject and may vary for a given subject over time, depending on the general medical condition of the subject. Similarly, the level of serum uric acid suitable for a group of subjects who share a common medical condition may be different from that which is appropriate for a different group of subjects who share a different medical condition. Therefore, it may be advisable to reduce the serum uric acid level of a given group of subjects to, for example, below about 5 mg / dL, and to reduce the serum uric acid level of a different group of subjects. a, for example, below about 4 mg / dl. In certain embodiments, the methods of the present disclosure decrease the level of serum uric acid in the subject in a sufficient amount to result in the disappearance, reduction, improvement or prevention of the occurrence of one or more conditions associated with a high level of uric acid in serum for a certain period of time, for example, about one week, about one month, about six months, about one year, about two years, or for a longer duration. For example, a method can decrease the level of serum uric acid in a subject in an amount sufficient to result in the disappearance or reduction of tophi for about a week, approximately one month, approximately six months, approximately one year, approximately two years, or more, p. eg, indefinitely, eg, for the rest of the subject's lifetime.

In other embodiments, the methods of the present disclosure comprise administering a pharmaceutical composition comprising a compound of Formulas (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof to a subject whose acid level serum uric acid is at least about 4 mg / dl, at least about 5 mg / dl, at least about 6 mg / dl, at least about 6.8 mg / dl, at least about 7 mg / dl, at least about 8 mg / dl, at least about 9 mg / dl, at least about 10 mg / dl, or at least about 11 mg / dl. Again, the amount of decrease in serum uric acid level that is adequate may vary depending on the subject, depending on the general medical condition of the subject. Similarly, the amount of decreased uric acid level in serum that is suitable for a group of subjects who share a common medical condition may be different from that which is appropriate for a different group of subjects who share a different medical condition.

The methods described herein (as well as the underlying physiological mechanisms related thereto) can be achieved by administration of a compound that generates the compound of Formula (IV) or a salt thereof through a chemical reaction after being administered. Said compounds include prodrugs of the compound of Formula (IV). Prodrugs of a compound are prepared by modifying the functional groups present in the compound such that the modifications can be cleaved in vivo to release the parent compound, or an active metabolite. For example, prodrugs include compounds in which a hydroxy, amino or sulfhydryl group in a compound is linked to any group that can be cleaved in vivo to regenerate the free hydroxyl, amino or sulfhydryl group, respectively. Certain prodrugs may increase the bioavailability of the compounds of the embodiments when said compounds are administered to a subject (eg, by allowing an orally administered compound to be absorbed more readily in the blood) or that improve the administration of the compound original to an organ or tissue (eg, adipose tissue, kidneys, liver, muscle or joints) in relation to the parent species. More particularly, prodrugs of the compound of Formula (IV) include esters, amides and carbamates (eg, N, N-dimethylaminocarbonyl) of the hydroxy functional group of the compound of Formula (IV). The compounds of Formulas (I), (II) and (III) are non-limiting examples of prodrugs of the compound of Formula (IV). Other examples of prodrugs can be found in J. Rautio et al. Prodrugs: design and clinical applications, Nat. Rev. Drug Discov., 7, 255-270 (2008); Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, (1987); and T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, vol. 14 of the ACS symposium series. (1975).

It is contemplated that the compounds of Formulas (I), (II), (III) and (IV) and pharmaceutically acceptable salts thereof will exhibit therapeutic activity when administered in an amount which may depend on the particular case. The variation in the quantity may depend, for example, on the subject to be treated and on the active ingredients chosen. A wide range of doses can be applied. Dosage regimens can be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily, weekly, monthly or others at appropriate time intervals or the dose may be proportionally reduced as indicated by the exigencies of the situation. Said doses are optionally altered depending on a series of variables, not limited to the activity of the one or more active principles used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition. to treat and the judgment of the doctor.

Depending on factors such as the diagnosis, symptoms and therapeutic objectives of a particular subject, a wide dose range of the compound of Formulas (I), (II), (III) or (IV) can be contemplated. In various embodiments, the compound can be administered from about 10 mg to about 1000 mg per day. For example, halofenate, halofenic acid or a pharmaceutically acceptable salt thereof can be administered at about 50 mg / day, about 100 mg / day, about 200 mg / day, about 300 mg / day, about 400 mg / day, about 500 mg / day, approximately 600 mg / day, approximately 700 mg / day, approximately 800 mg / day, approximately 900 mg / day, or approximately 1000 mg / day.

Dosage adjustment or dose increase protocols may be employed to determine the appropriate or optimal dose to be administered to a subject. For example, studies of adjustment or dose increase can be selected for doses that improve efficacy or tolerability. The adjustment or increase of the dose allows the gradual adjustment of the administered dose until achieving the desired effect. The dose adjustment gradually decreased the dose administered, while increasing the dose gradually increases the dose administered. Methods of adjustment and dose increase are well known in the art. As a non-limiting example, a subject can be administered 200 mg / day of halofenate, halofenic acid or a pharmaceutically acceptable salt thereof every day and serum uric acid levels can be measured daily. The dose can be increased or decreased, for example, weekly. The subject can be monitored for a period of, for example, 2 to 12 weeks to find the desired dose.

The compounds of Formula (I), (II), (III) or (IV) can be incorporated into various formulations and medicaments for therapeutic administration. More particularly, these compounds can be formulated into pharmaceutical compositions or formulations by combination with pharmaceutically acceptable carriers or diluents, and can be formulated into solid, semisolid, liquid or gaseous forms, such as tablets, capsules, pills, powders, granules, dragees, gels, pastes, ointments, solutions, suppositories, injections, inhalants and aerosols. As such, the administration of the compounds can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal or intratracheal administration. In addition, the compound can be administered locally rather than systemically, in a depot or sustained release formulation. In addition, the compounds can be administered in a liposome.

The compounds of Formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof can also be formulated with common excipients, diluents or vehicles and compressed into tablets, or formulated as elixirs or solutions for a convenient oral administration, or administered intramuscularly or intravenously. The compounds may be administered transdermally, and may be formulated as sustained release dosage forms and the like. The above methods may further comprise the administration of a second urate reducing agent selected from the group consisting of a xanthine oxidase inhibitor, an uric acid production inhibitor, an uricosuric agent and an uricase. The method may comprise administering a pharmaceutical composition comprising a first urate reducing agent and a second therapeutic agent, as described herein, to a subject whose serum uric acid level is at least about 4 mg / dl, at at least about 5 mg / dl, at least about 6 mg / dl, at least about 6.8 mg / dl, at least about 7 mg / dl, at least about 8 mg / dl, at least about 9 mg / dl, at less about 10 mg / dl, or at least about 11 mg / dl. The amount of decrease in serum uric acid level that is adequate may vary depending on the subject, depending on the general medical condition of the subject. Similarly, the amount of decreased uric acid level in serum that is suitable for a group of subjects who share a common medical condition may be different from that which is appropriate for a different group of subjects who share a different medical condition. The application provides combination therapy and methods of co-administration of a first and second urate reducing agent (wherein these first and second urate reducing agents are described herein). Combination therapy and co-administration refer to the administration of the two agents (ie, a first agent and a second urate reducing agent, as described herein) in any manner in which the pharmacological effects of both they manifest in the subject at the same time. Therefore, such administration does not require that a single pharmaceutical composition, the same type of formulation, the same pharmaceutical form or even the same route of administration be used for the administration of the first and second urate reducing agents, or that the two agents are administered at the same time. Said administration can be carried out more conveniently by the same pharmaceutical form and the same route of administration. administration, substantially at the same time. For example, a first urate reducing agent, for example, halofenate, halofenic acid or a pharmaceutically acceptable salt thereof, and a second urate reducing agent, eg, a xanthine oxidase inhibitor (eg, allopurinol or febuxostat), can be administered to the human subject together in an individual oral dosage composition, such as a tablet or capsule, or each agent can be administered in separate oral pharmaceutical formulations. An advantage with separate formulations is an additional flexibility in the dosage, that is, the dosage of the first and second urate reducing agents can be changed independently, quickly and easily. When separate pharmaceutical formulations are used, the first and second urate reducing agents can be administered essentially at the same time (i.e., simultaneously or concurrently), or at staggered times separately (i.e., sequentially). In another embodiment, the second urate reducing agent is a xanthine oxidase inhibitor, preferably selected from the group consisting of allopurinol, febuxostat, oxipurinol, tisopurine, inositol, phytic acid, myoinositol, kaempferol, myricetin and quercetin, especially allopurinol. or febuxostat. In yet another embodiment, the second urate reducing agent is allopurinol and is administered from about 50 mg to about 800 mg per day. In another embodiment, the first urate reducing agent is (-) - halofenate and is administered from about 100 mg to about 600 mg per day, and the second urate reducing agent is febuxostat and is administered from about 40 mg to about 120 mg per day. In another embodiment, the second urate reducing agent is an uricosuric agent, preferably selected from the group consisting of probenecid, 2 - ((5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1 acid. , 2,4-triazol-3-yl) thio) acetic acid, 4- (2 - ((5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazole-3-) il) thio) acetamido) -3-chlorobenzoate potassium, RDEA684, benzbromarone, sulfinpyrazone, amlodipine, atorvastatin, fenofibrate, guaifenesin, losartan, adrenocorticotropic hormone and cortisone, especially probenecid.

In various embodiments, the compounds of Formula (I), (II), III) or (IV) or a pharmaceutically acceptable salt thereof can be administered over a wide range of frequencies. For example, in various embodiments, the compounds may be administered once a day (QD), twice a day (BID), three times a day (TID) or four times a day (QID). In one embodiment, the compound is administered once a day (QD). In another embodiment, the compound is administered twice a day (BID). In other embodiments, the administration of the compound can be omitted without having a deleterious effect, ie, the compound can be administered (ie, before and after) a "pharmacological rest" in which the pharmacological rest is the period of the omitted dose . For example, in a daily dosage regimen, the compound can be administered during a one-day pharmacological course, (ie, administered on day N and day N 2 but not on day N + 1, in which day N is any arbitrary day) without the subject experiencing any substantial adverse or material effects of the omitted administration. In certain embodiments, the pharmacological rest can be two days. In other embodiments, the pharmacological rest may be more than two days.

In various embodiments, the compounds of Formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof can be administered for a broad duration. For example, in various embodiments, the compounds may be administered for about four weeks or more, approximately one month or more, approximately three months or more, for approximately six months or longer, for approximately one year or longer, for approximately two years or more. , for approximately five years or more, or for approximately ten years or more. In some embodiments, the administration may be undefined, eg, for the remainder of the subject's lifetime.

The pharmacokinetic profile of (-) - halofenic acid can be modulated by the dose, frequency and duration of administration of the compound or a prodrug thereof. A measure of the pharmacokinetic profile is the maximum to trough ratio, defined as the highest blood plasma concentration divided by the lowest blood plasma concentration of a compound or agent within a certain time interval (eg, within the range corresponding to the frequency of administration). For example, certain methods include providing a subject with an intraday maximum to (h) halofenic acid ratio of about 2.0 or less, which comprises administering to the subject a compound of Formulas (I), (II), ( III) and (IV) or pharmaceutically acceptable salts thereof in a dose of about 100 to about 1000 mg per day. In various embodiments, the ratio of maximum to intraday valley is about 1.7 or less, about 1.5 or less, about 1.4 or less, or about 1.3 or less. In embodiments, the maximum intra-valley ratio is provided after the compound is administered daily for at least about 10 days, for example, at least about 12 days. The pharmacokinetic profile may also depend on the route of administration, as well as the compound and formulation administered to the subject. For example, one method includes providing a subject with an intraday maximum to (h) halofenic acid ratio of about 2.0 or less, which comprises administering the subject arhalophenate (ie, (-) - halofenate) via orally in an oral formulation (eg, a tablet, capsule, pill, etc. as described above) at a dose of 100 to 1000 mg per day.

Certain methods described herein may be carried out by administering a compound of Formulas (I), (II), (III) and (IV) or pharmaceutically acceptable salts thereof at a given dose, frequency and duration of administration, as provided in the present document. For example, certain methods provide for the treatment of hyperuricemia in a subject with droplet comprising administering to a subject in need thereof a compound of Formula (I), (II), (III) and (IV) or pharmaceutically acceptable salts thereof. where the Dosage, frequency and duration of administration are effective to reduce the number, duration, frequency or intensity of gout outbreaks experienced by the subject during the duration. In some embodiments, the compound is arhalophenate. In some embodiments, the dose is from about 100 mg to about 1000 mg. In some embodiments, the frequency is daily. In some embodiments, the duration is approximately four weeks or more. In other embodiments, the duration is about one month or more, about three months or more, about six months or more, about one year or more, about two years or more, about five years or more, or about ten. years or more In some embodiments, the administration may be undefined, eg, for the remainder of the subject's lifetime. In some embodiments, daily administration and during a one-day pharmacological break. In some embodiments, it further comprises administering the subject arhalophenate orally in an oral formulation. Particular embodiments including compositions, formulations and their method of use are disclosed in a PCT patent application entitled "Methods for Treating Hyperuricemia in Patents with Gout Using Halofenate or Halofenic Acid and a Second Urate-Lowering Agent" filed in conjunction with the present application. . The embodiments of this application are characterized by the specification and by the features of the claims of this application, and of the corresponding pharmaceutical compositions, methods and uses of these compounds.

Methods

The methods used in relation to Figures 1-2 showing the pharmacokinetic profile of (-) - halofenic acid were the following:

Plasma proteins in human plasma samples containing (-) - halofenic acid, an internal standard (PI) and heparin as an anticoagulant were precipitated with acetonitrile. The samples were mixed with a vortex shaker, centrifuged and an aliquot analyzed by reverse phase high performance liquid chromatography using a Phenomenex Polar RP column maintained at 45 ° C. The mobile phase was nebulized using nitrogen heated in a Z spray interface / source and the ionized compounds were detected using a tandem quadrupole mass spectrometer.

Plasma concentrations were rounded to the nearest tenth pg / ml before calculations. Plasma samples with concentrations below the quantifiable limit of 1.0 pg / ml (BQL) were assigned zero values.

The methods used in relation to Fig. 3 that show a reduction in serum uric acid in subjects over time after a daily dose with arhalophenate were the following.

A phase 1, double-blind, randomized, placebo-controlled, double-blind, dose-increasing study (MAD study, MBX102-2DM01011b) was performed to evaluate the pharmacokinetics (PK) of multiple doses of (-) - halofenate administered as a daily dose orally for 10 days, at the doses specified in the protocol in healthy adult subjects. A total of 119 subjects completed the study treatment according to the protocol: 6 subjects received MBX-102 100 mg / day for 10 days; 6 subjects received MBX-102 200 mg / day for 10 days; 9 subjects received MBX-102400 mg / day for 10 days; 20 subjects received MBX-102600 mg / day for 10 days; 10 subjects received MBX-102 600 mg of enteric coating (RE) / day for 10 days; 9 subjects received MBX-102 800 mg RE / day for 10 days; 10 subjects received MBX-102 1000 mg RE / day for 10 days; 24 subjects received placebo treatment daily for 10 days; and 25 subjects received monotherapy with naproxen 500 mg bid for 7 days. In this study, serum uric acid was measured in the selection and on days 1, 3, 5, 7, 9, 14 and 21.

T l 1

As shown in Fig. 3 and Table 1, data from study MBX102-2DM01011b demonstrate that treatment with (-) - halofenate resulted in a gradual reduction of uric acid in serum over a period of time at all dose levels tested, and in a dose-dependent manner.

The methods used in relation to Fig. 4-5 showing the effects of IL-1 p on (-) - halofenic acid were the following:

Eight-week-old male C57BL / 6J mice were injected intraperitoneally with 2.5 ml of 3% thioglycollate. Three days after the injection, the mice were sacrificed by cervical dislocation. The macrophages were immediately collected by injecting 5 ml of PBS into the intraperitoneal cavity, surgically exposing the intraperitoneal cavity and aspirating the intraperitoneal fluid with a 1 ml syringe. The macrophages from multiple animals were pooled and centrifuged at 1500 rpm, 10 min at 4 ° C. The contaminating red blood cells were removed from the pellet by lysis with 10 ml of RBC lysis buffer for 5 min at room temperature, followed by centrifugation at 1500 rpm, 10 min at 4 ° C. The cells were washed once and resuspended in RPMI 1640, 10% SFB / 0.1% Pen / Strep and placed in multi-well plates (1,000,000 cells / well for 24-well plates and 100,000 cells / well). well for 96-well plates). Cells were cultured for 30 hours, re-fed with fresh RPMI 1640, 0.5% SFB and incubated overnight. The cells were treated for 1 hour with DMSO, (-) - halofenic acid (75 and 150 pM) and then stimulated with 100 ng / ml of LPS for 8 more hours. After stimulation with LPS, the cell supernatants were then harvested and stored at -200 ° C prior to analysis of secreted cytokine levels using a Procarta ™ cytokine profile kit (Panomics Inc., Fremont, CA).

Cells were harvested in Qiazol lysis solution for analysis of gene expression. The RNA was isolated (using the MagAttract Universal Tissue M48 RNA kit according to the manufacturer's instructions), the cDNA was prepared by reverse transcription (using the high capacity reverse transcription kit of the cDNA according to the manufacturer's instructions) and the PCR-TI (Taqman) was performed in 96-well PCR plates using a gene expression assay mixture for IL-1 p (ABI cat no .: Mm00434228_m1) and Taqman rapid universal master PCR mixture. The Ct values for lL-1 p were determined using the ABI sequence detection software. The expression of the gene "relative level of change with respect to LPS" was calculated using the comparative Ct method for relative quantification as suggested by ABI (Foster City, CA). This method involved comparing the Ct values of the samples pretreated with the LPS compound with the samples treated with LPS vehicle. The Ct values of the samples treated with the compound and with the vehicle were normalized with respect to the endogenous constitutive gene (GAPDH). This method is also known as the 2A- [delta] [delta] Ct method, where [delta] [delta] Ct = [delta] Ct (sample) - [delta] Ct (reference). In this case, [delta] Ct (sample) is the value of Ct for the sample treated with the compound normalized to the endogenous constituent gene and [delta] Ct (reference) is the Ct value for the sample treated with the vehicle normalized to endogenous constitutive gene. The level of change is calculated using the formula 2A- [delta] [delta] Ct. Each experimental condition was run in 4 replicate wells. The data of the "relative change level with respect to LPS" from the repeated experiments were pooled and the significance was tested using 1-way ANOVA with Tukey post hoc test (* = p <0.05, ** = p <0 , 01 and *** = p <0.001).

The data presented in Fig. 6 and 7 were generated on the basis of a single-dose, randomized, single-blind, phase 1, multiple-dose study (M102-0507) that evaluated the effect of (-) - halofenate administered to diabetic patients type 2 who were receiving a stable dose of Glynase ® (micronized glyburide). Eligible patients were initially given a dose of Glynase® 3 mg / day for 3 days, and if the researcher accepted safety and tolerability, the dose was increased to Glynase® 6 mg / day for 4 days, followed by 14 days of Glynase® 6 mg and any administration of (-) - halofenate 400 mg or 600 mg until day 21, patients were discharged on day 22. This scheme is summarized in Table 2.

In this study, the change in high sensitivity C-reactive protein (hs-CRP) from the initial period was one of the endpoints. It was observed that hs-CRP increased from day 1 to day 8 (20.8% in group 1 and 15.6% in group 2), and then decreased between days 8 and 22. On day 22 , mean percentage changes in C-reactive protein compared to day 1, were -21.1% and -32.9% in group 1 ((-) - halofenate 400 mg) and group 2 ((- ) -halphaena 600 mg), respectively.

T l

As shown in Fig. 6-7 and Table 3, data from study M102-10507 demonstrate that treatment with (-) - halofenate at a daily dose of 600 mg significantly reduced hs-CRP from day 1 ( initial period) and from day 8 (glyburide phase only). The mean changes of hs-CRP were: 32.9% (p = 0.0091) and -33.3% (p = 0.0214), respectively.

Examples

Example 1: Suppression of inflammation induced by uric acid in vitro

The differentiated murine 3T3-L1 adipocytes are cultured in vitro in 24-well plates. To the culture medium, (-) - halofenic acid is added to a final concentration of 50-150 μM before the addition of uric acid at 5 mg / dl or 15 mg / dl and the culture continues for 3 or 7 days. A parallel culture of cells is carried out in the presence of a vehicle such as dimethyl sulfoxide (DMSO). At the end of the culture period, the media are removed, the cells are isolated and the messenger RNA is prepared. Levels of secreted cytokines representing a panel of proinflammatory cytokines including, but not limited to, monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor a (TNF-a), interleukin-1p, (IL-1 p ), interleukin-6 (IL-6) and interleukin-12 (Il-12) are determined in the isolated media of the cells using commercially available cytokine assay kits. Gene expression levels for mRNAs for a panel of proinflammatory cytokines including, but not limited to, monocyte chemoattray protein 1 (MCP-1), tumor necrosis factor a (TNF-a), interleukin-1p, (IL-1) p), interleukin-6 (IL-6) and interleukin-12 (Il-12) are determined using real-time PCR. The addition of (-) - halofenate prevents the absorption of uric acid in 3T3-L1 adipocytes and, therefore, suppresses the inflammatory response induced by uric acid which results in a reduced level of expression and, consequently, the secretion of this panel of proinflammatory cytokines. A similar study is also performed on primary mouse macrophages and human umbilical vein endothelial cells.

Example 2: Animal drop bud model

The models described in R. Torres et al., Ann. Rheum. Dis. 68, 1602-08 (2009) (available at http://ard.bmj.com/content/68/10/1602.long). Briefly, twenty C57BL6 mice were obtained from Jackson Laboratories (Bar Harbor ME USA) and used between the ages of 12 and 16 weeks. The mice are housed individually at least one week before the study and are allowed access to regular food and water at their discretion. Arhalofenate is orally administered to half (ten) of the mice (test mice) daily at a dose of 125 mg / kg for periods of time including, for example, 1 day, 5 days and 2 weeks before the induction of inflammation by uric acid. The remaining 10 mice (control mice) are administered a vehicle consisting of 1% carboxymethylcellulose // 2% Tween-80. In another treatment modality, arhalophenate is co-administered at the time of treatment with uric acid.

The monosodium urate crystals (UMS) are prepared as described in R. Liu-Bryan et al., Arthritis Rheum. 52, 2936-46 (2005). In one model, UMS crystals (0.5 mg) suspended in 20 microliters of endotoxin-free PBS are injected into the tibio-tarsal joint (ankle) of mice anesthetized with 2.5% isoflurane. The thermal hyperalgesia, the weight bearing capacity, the diameter of the angle joint and the histological analyzes are performed according to Torres et al, cited above. The level of secretion of a panel of proinflammatory cytokines including, without restriction, monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor a (TNF-a), interleukin-1p, (IL-1 p), interleukin -6 (IL-6) and interleukin-12 (Il-12) are measured in a liquid isolated from the injected joints. The junctions are dissected and homogenized to allow preparation of the mRNA and the level of gene expression of the same panel of proinflammatory cytokines is determined. In another model, the mice are injected intraperitoneally with 1 mg of UMS suspended in 0.5 ml of endotoxin-free PBS. After 6 h, the mice are sacrificed and their peritoneal cavities are washed and collected to measure the neutrophil influx by staining with an anti-mouse Ly-6G rat monoclonal antibody conjugated to neutrophil R-phycoerythrin. In another model, an air bag is introduced subcutaneously and 1 mg of UMS is injected into the bag. Six hours after the injection of the crystal, the cells residing in the bag are collected by washing them with 5 ml of buffer. Neutrophil infiltration is measured by staining as indicated above. The levels of monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor a (TNF-a), interleukin-1p, (IL-1 p), interleukin-6 (IL-6) and interleukin-12 (Il -12) are also measured in the isolated washing liquid of the injected urate air bag.

Example 3: Clinical trial comparing the effectiveness of arhalofenate in the reduction of gout flares during the initiation and maintenance of the use of therapy for the reduction of uric acid

This is a double-blind, parallel group, multicenter and randomized study.

Main evaluation criterion

Proportion of patients who experienced an outbreak of acute gout in general and in the time periods separated from weeks 0-2 of treatment, weeks 3-12 of treatment and weeks 11-12 of treatment.

Secondary endpoints:

to. Total number of drop buds

b. Duration of gout shoots

c. Incidence of patient abandonment due to gout outbreaks.

d. Gravity of drop buds

Treatment guideline:

Individuals are randomized into three groups: one control group (n = 100) and two experimental groups (n = 100 each). Allopurinol (300 mg) is administered once a day to subjects in the control group. Subjects of the experimental groups are administered arhalophenate tablets (400 mg or 600 mg) once a day. All patients receive outbreak prophylaxis during the first two weeks of treatment. The duration of treatment with the drug in the blind study is three months.

Inclusion criteria:

Man or woman, over 18 years old.

Women of childbearing age should have a negative pregnancy test. Female individuals of childbearing age should be infertile or use contraception.

Serum uric acid> 6.0 mg / dl and <12 mg / dl

Diagnosed with gout according to the criteria of the ARA of 1980 for the classification of acute arthritis of primary gout.

Analysis:

The primary analysis is based on a comparison between the control group and the arhalophenate groups in the proportion of subjects who experienced an outbreak using an intention-to-treat approach. Pairwise comparisons between groups are made using Fisher's exact test.

Although the foregoing description describes specific embodiments, those skilled in the art will appreciate that various modifications and alternatives may be developed. Accordingly, the particular embodiments and examples described above are intended to be illustrative only, and do not limit the scope of the invention, which must be provided with the full scope of the appended claims.

Claims (15)

A compound that is (-) - halofenate, or (-) - halofenic acid or a pharmaceutically acceptable salt thereof, substantially free of its (+) enantiomer, for use in the treatment of a drop outbreak or to reduce the number, frequency, duration or intensity of outbreaks of gout experienced by a subject during the initiation or maintenance of therapy to reduce uric acid. 2. The compound for use according to claim 1 which is for treating a gout outbreak. 3. The compound for use according to claim 1, which is to reduce the number, frequency, duration or intensity of drop sprouts. 4. The compound for use according to any one of claims 1 to 3 wherein the compound is (-) - halofenate. The compound for use according to any one of claims 1 to 3 wherein the compound is (-) - halopeneic acid or a pharmaceutically acceptable salt thereof. 6. The compound for use according to any one of claims 1 to 5 wherein the compound is administered orally. The compound for use according to any one of claims 1 to 6 wherein the amount of the compound is effective for the dose once a day. The compound for use according to any one of claims 1 to 7 wherein the compound is administered from 100 to 1000 mg / day, preferably at 400, 600, 800 or 1000 mg / day. The compound for use according to any one of claims 1 to 8 wherein the compound is administered for four weeks or more. The compound for use according to any one of claims 1 to 9 wherein the subject is one being treated or requiring treatment with a prophylaxis agent of the outbreak or a pain treatment agent. 11. The compound for use according to claim 10 wherein the prophylaxis agent of the outbreak or the pain treatment agent is colchicine. The compound for use according to any one of claims 1 to 9 wherein the subject is also administered a urate reducing agent which is an inhibitor of xanthine oxidase, an inhibitor of uric acid production, an agent uricosuric or uricasa. 13. The compound for use according to claim 12 wherein the urate reducing agent is allopurinol or febuxostat. The compound for use according to claim 12 or 13 wherein the urate reducing agent is febuxostat. 15. The compound for use according to claim 12 wherein the urate reducing agent is probenecid, benzbromarone, or sulfinpyrazone.